Cannula system

ABSTRACT

The present disclosure provides a cannula useful for introducing a thermally responsive polymer in situ. In embodiments, the cannula possesses more than one cannula, with the thermally responsive polymer introduced in one cannula, and a material such as a coolant in a second cannula which prevents premature gelling of the thermally responsive polymer.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application claims the benefit of and priority to U.S. ProvisionalPatent Application No. 60/963,049, filed Aug. 2, 2007, the entiredisclosure of which is incorporated by reference herein.

TECHNICAL FIELD

The present disclosure relates to cannulas suitable for introducingthermoreversible polymeric materials in situ.

BACKGROUND OF RELATED ART

A polyp is generally a growth that projects from a membrane in the body.The shape of a polyp is often described as pedunculated or sessile.Pedunculated polyps grow on stalks, while sessile polyps may have broadbases and a flat appearance. Often, polyps form on mucous membranes suchas those lining the colon, bladder, uterus, cervix, vocal cords, and/ornasal passage and protrude into a body cavity. Polyps are problematic inthat they may block a passage, and/or may become cancerous. Generally,the larger the polyp, the more likely it is to become cancerous.

Endoscopic polypectomy procedures are effective in removing pedunculatedpolyps; however, sessile polyps are often problematic. For example,because of their flat, diffuse appearance, sessile polyps may bedifficult to snare and excise with electrocautery. To facilitateexcision of some polyps, saline may be injected into the submucosa of apolyp to create an artificial cushion that raises the polyp. However,saline has a short residence time in the submucosa: it usually clearswithin 4 to 5 minutes after injection.

In addition, large polyps are often difficult to remove as a whole, sothey are often excised in piecemeal fashion. After the first excision ofpolyp tissue, injected solution may escape from the submucosa causingthe polyp to collapse, thus making it difficult to remove the remainingportions of the polyp. Although saline may be re-injected, it escapesquickly and is not very effective in raising the remaining portions ofthe polyp.

Attempts to improve submucosa residence time of injection solutions havebeen reported. For example, solutions of glycerin, dextrose, hyaluronicacid, and hydroxpropyl cellulose have been reported as injectionsolutions. In some cases, hyaluronic acid may be effective. The averageresidence time of hyaluronic acid solutions in porcine esophagus isreportedly 21.5 minutes. However, these solutions may still leak out ofthe submucosal layer once the cushion is breached during the endoscopicdissection or polypectomy.

Means for introducing injection solutions into a polyp includeendoscopic methods which may, in embodiments, include the use ofcatheters and/or cannulas. As is within the purview of those skilled inthe art, cannulas may include tubular, flexible, surgical instrumentsfor withdrawing fluids from (or introducing fluids into) a cavity of thebody. Cannulas may have a single lumen or may have multiple lumens;multi-lumen cannulas, including dual lumen cannulas, are also within thepurview of those skilled in the art.

Various configurations multi-lumen catheters and/or cannulas are alsoknown. For example, U.S. Pat. No. 4,385,631 discloses a hemodialysiscatheter having two circular lumens arranged side by side. U.S. Pat. No.4,099,528 discloses a coaxial double lumen cannula and U.S. Pat. No.4,493,696 describes a coaxial double lumen catheter.

There remains room for improvement in compositions and methods forperforming endoscopic polypectomy procedures, as well as instrumentssuitable for introducing polymeric materials into the body.

SUMMARY

The present disclosure provides multi-lumen cannulas suitable forintroducing thermally responsive polymers in situ. Such multi-lumencannulas may include, in embodiments, a proximal end and a distal end,at least one lumen configured to permit the passage of a coolant, and atleast one additional lumen configured to permit the passage of acomposition including a thermally responsive polymer, wherein thethermally responsive polymer is in a low viscosity state at apre-treatment temperature and a higher viscosity state at a treatmenttemperature that is higher than the pre-treatment temperature.

In embodiments, cannulas of the present disclosure may be utilized tointroduce thermally responsive polymers into polyps to aid in theirremoval.

Methods for applying compositions with these devices are also provided.In embodiments, methods of the present disclosure may include obtaininga composition including a thermally responsive polymer, wherein thecomposition is in a low viscosity state at a pre-treatment temperatureprior to being injected into a polyp and a higher viscosity state at atreatment temperature that is higher than the pre-treatment temperature.The compositions may be administered to the polyp using a multi-lumencannula including a proximal end and a distal end, at least one lumenconfigured to permit the passage of a coolant, and at least a secondlumen configured to permit the passage of the composition including thethermally responsive polymer. The composition may be warmed therebyincreasing the composition's viscosity to the higher viscosity state,and the polyp may be removed while the composition including thethermally responsive polymer remains substantially inside the polyp.

BRIEF DESCRIPTION OF THE DRAWINGS

Various embodiments of the present disclosure will be described hereinbelow with reference to the figures wherein:

FIG. 1 is a cross section of a cannula of the present disclosure havingan inner lumen capable of carrying a thermally responsive polymer and anouter lumen capable of carrying a coolant;

FIG. 2 is a depiction of a cannula of the present disclosure possessinga needle therein;

FIG. 3 is another depiction of a cannula of the present disclosurepossessing a needle therein with the proximal end of the cannulaattached to a double-lumen syringe; and

FIG. 4 is another depiction of a cannula of the present disclosurepossessing a needle therein, a double-lumen syringe attached to theproximal end of the cannula, and a valve, stopper or seal at the distalend of the cannula.

DETAILED DESCRIPTION

The present disclosure provides cannulas suitable for introducingcompositions containing one or more thermally responsive polymers intothe body. In embodiments, the compositions may be in a low viscositystate such as a liquid at a pre-treatment temperature, and a higherviscosity state such as a gel at a treatment temperature that is higherthan the pre-treatment temperature.

In accordance with the present disclosure, a multi-lumen cannula may beutilized to introduce the composition containing one or more thermallyresponsive polymers into the body. The composition containing one ormore thermally responsive polymers may be introduced into the bodythrough at least one lumen, with at least one other lumen of themulti-lumen cannula containing a coolant which prevents prematuregelling of the thermally responsive polymer as it is introduced into thebody or at any injection site.

A multi-lumen cannula for use in accordance with the present disclosureshould possess at least two lumens. In embodiments, as noted above, atleast one lumen may contain a coolant, with at least one other, lumenpossessing the thermally responsive polymer composition. In otherembodiments, the cannula may possess additional lumens which may houseand permit the transit of other suitable items and/or devices including,but not limited to, one or more medicines, drugs, blood, medicaldevices, guide wires, snares suitable for use in polypectomy procedures,needles, optical fibers, fiber optic imaging devices, fiber opticdiagnostic probes, combinations thereof, and the like.

In embodiments, a suitable multi-lumen cannula may be a double lumencannula. A double lumen cannula may possess any configuration within thepurview of those skilled in the art. For example, in some embodiments, asingle tube with a horizontal division of the tube which places thelumens of the cannula in immediate juxtaposition may be utilized.

In other embodiments, a coaxial double lumen cannula may be utilized tointroduce the composition containing one or more thermally responsivepolymers into the body. Such a cannula may possess concentric lumens,disposed one within the other. A cross-section of such a cannula, whichshould be apparent to one skilled in the art, is depicted in FIG. 1. Asdepicted in FIG. 1, cannula 10 may include two lumens, inner cannulalumen 12 and outer cannula lumen 14. Inner wall 16 may encompass innerlumen 12, while outer wall 18 may encompass outer lumen 14. The diameterof the inner lumen may be from about 1 mm to about 2 mm, in embodimentsfrom about 1.25 mm to about 1.75 mm. The diameter of cannula 10 may beless than about 2.8 mm, in embodiments from about 2.2 mm to about 2.8mm.

The composition containing one or more thermally responsive polymers maybe introduced into the body via the inner lumen or the outer lumen; theother lumen may contain a coolant to prevent premature gelling of thethermally responsive polymer. For example, the composition containingone or more thermally responsive polymers may be introduced into thebody via the outer lumen with the coolant contained in the inner lumen.In other embodiments, the composition containing one or more thermallyresponsive polymers may be introduced into the body via the inner lumen,with the coolant being present in the outer lumen of the cannula.

A cannula in accordance with the present disclosure may be of anysuitable length; in embodiments from about 1 meter to about meters long,in other embodiments from about 1.25 meters to about 2.3 meters long.

The cannulas of the present disclosure may be utilized to deliverthermally responsive polymers endoscopically through a conventionalcolonoscope. Accordingly, while a cannula of the present disclosure maybe constructed of any material within the purview of those skilled inthe art, in embodiments a cannula of the present disclosure may beconstructed of a comparatively soft medical grade plastic or metals suchas stainless steel, titanium, and the like. Specific synthetic materialswhich may be utilized include, but are not limited to, fluoropolymersincluding polytetrafluoroethylene, polyurethane, polyethylene,polypropylene, high density polyethylene, nylons, polyethyleneterephthalate, silicones, combinations thereof, and the like.

In embodiments, the inner lumen of the cannula may possess a Luer lockfitting at one end and a short dispensing needle at the other end, i.e.,the distal end, having a length of from about 3 mm to about 8 mm, inembodiments about 4 mm, with a gauge of from about 14 gauge to about 23gauge, in embodiments from about 18 gauge to about 21 gauge. An exampleof such a cannula is depicted in FIG. 2. Cannula 10 may possess outertube 18 surrounding outer cannula lumen 14, inner tube 16 surroundinginner cannula lumen 12, with needle 40 affixed to the distal end ofinner tube 16 adjacent distal end 20 of cannula 10. Outer tube 18functions as a protective sheath to protect the needle and provide aworking channel for any scope utilized therewith (not shown). The outerdiameter of outer tube 18 may be of a suitable size, in embodiments lessthan or equal to about 2.7 mm. The diameter of the inner tube 16 issmall enough to permit passage within outer tube 18. The inner diameterof inner tube 16 may be, in embodiments, from about 1 mm to about 2 mm.Needle 40 may, in embodiments, be from about 14 gauge to about 23 gauge,and may be of a length of from about 3 mm to about 8 mm. A thermallyresponsive polymer may be introduced into inner tube 16 at its proximalend 50 adjacent proximal end 30 of cannula 10 utilizing a luer locksyringe, a mechanically advancing gun, or similar device (not shown).

In embodiments, the distal end of the outer lumen of the cannula may beopen. Where a coolant is present in the outer lumen of the cannula, aseparate port with a luer lock fitting may be utilized to inject thecoolant into the outer lumen or the same port may be utilized tosimultaneously inject both the thermally responsive polymer and thecoolant. Where the same port is utilized to simultaneously inject boththe thermally responsive polymer and the coolant, a double-lumen syringemay be utilized with one compartment containing the polymer solution forintroduction into the inner lumen and a second compartment containingthe coolant for introduction into the outer lumen. An example of such acannula is depicted in FIG. 3. As set forth in FIG. 3, cannula 10,possessing outer tube 18, inner tube 16, and needle 40 at the distal endof inner tube 16 within distal end 20 of cannula 10, may have a closedproximal end 60 and access ports 70 and 75 which may be connected to adouble-lumen syringe 80, possessing lumens 85 and 90. Lumen 85 maypossess a thermally responsive polymer which may be introduced viaaccess port 70 into inner cannula lumen 12, while lumen 90 may possess acoolant which may be introduced via access port 75 into outer cannulalumen 14. Double lumen syringe 80 may possess backing 100 on plungers110 and 120 to facilitate the simultaneous introduction of the thermallyresponsive polymer and the coolant. In either case, the polymericmaterial may be introduced into the body via the inner lumen which may,in embodiments, have a needle 40 as described above attached thereto;the coolant may be dispensed out of the distal end of the cannula intothe body, for example the colon, where the cannula is utilized tointroduce the thermally responsive polymer into a polyp during apolypectomy.

In yet other embodiments, the distal end of the outer lumen of thecannula may be closed so that the coolant is not discharged into thebody. In this embodiment, a valve, stopper, seal, or similar device maybe placed at the distal end of the outer lumen which prevents thecoolant from exiting the distal end of the cannula. An example of such acannula is depicted in FIG. 4. As set forth in FIG. 4, cannula 10,possessing outer tube 18, inner tube 16, and needle 40 at the distal endof inner tube 16 within distal end 20 of cannula 10, may have a closedproximal end 60 and access ports 70 and 75 which may be connected to adouble-lumen syringe 80, possessing lumens 85 and 90. Lumen 85 maypossess a thermally responsive polymer which may be introduced viaaccess port 70 into inner cannula lumen 12, while lumen 90 may possess acoolant which may be introduced via access port 75 into outer cannulalumen 14. Double lumen syringe 80 may possess backing 100 on plungers110 and 120 to facilitate the simultaneous introduction of the thermallyresponsive polymer and the coolant. Cannula 10 may possess a stopper,valve, or seal 130 at its distal end 20 which permits passage of needle40 therethrough but prevents any coolant from exiting outer cannulalumen 14. In embodiments, it may be desirable to determine the volume ofthe outer lumen and introduce that amount of coolant therein, tominimize backflow of the coolant from the proximal end of the cannuladuring a surgical procedure.

Any coolant capable of preventing premature gelling of the thermallyresponsive polymer may be utilized. Suitable coolants which may beincluded in one of the lumens, in embodiments the outer lumen, include,for example, cooled liquids such as water, saline, ethanol, combinationsthereof, and the like, and/or cooled gases such as air, nitrogen, argon,helium, carbon dioxide, combinations thereof, and the like. In somecases, gases may be cooled to a liquid state, for example, liquidnitrogen.

In other embodiments, suitable coolants may include solutions such asammonium nitrate crystals in water, which are capable of dissolving inwater while absorbing heat and cooling their surroundings in a fewseconds. Similar solutions which may be utilized as the coolant include,but are not limited to, potassium iodide in water, ammonium chloride inwater, ammonium acetate in water, potassium thiocyanate in water,ammonium thiocyanate in water, sodium thiosulfate in water, ammoniumbromide in water, combinations thereof, and the like. Other solutionswhich may be utilized as a coolant include urea based solutionscommercially available as INSTAKOOL™ from Nortech Laboratories, Inc.(Farmingdale, N.Y.), and the like. In addition, combinations ofchemicals known to produce endothermic reactions, for example, bakingsoda with citric acid, and the like, may be combined and utilized as acoolant.

Combinations of the above-identified coolants may also be utilized insome embodiments.

In embodiments, the above coolants may be utilized without any externaltemperature control. In other embodiments, the temperature of thecoolant may be adjusted utilizing external means, for example, asuitable control system such as a Peltier cooler, a Joule-Thompsoncryostat, a Stirling engine, an independent closed-loop refrigerationsystem, and the like. Such temperature control systems and theiroperation are within the preview of those skilled in the art.

Thermally responsive polymers which may be utilized with the cannula ofthe present disclosure may include one or more polymeric substances thatundergo a change in viscosity with a change in temperature, for example,warming. In embodiments, the thermally responsive polymers may be in asolution including at least one solvent, with other excipients and/oringredients to form a composition of the present disclosure. Inembodiments, additional excipients and/or ingredients may be added tofacilitate usage of the compositions and adjust their viscosity, forexample, during a polypectomy procedure. As used herein, “viscosity”refers to a measure of the resistance of a fluid to deform under shearstress and is used herein to describe a fluid's internal resistance toflow. For example, water has a relatively lower viscosity, whilesubstances like vegetable oil or honey have a higher viscosity.

Compositions utilized in accordance with the present disclosure mayinclude a pharmaceutically acceptable carrier or diluent, vehicle ormedium, for example, a carrier, vehicle or medium that is compatiblewith the tissues to which they will be applied. The term“dermatologically or pharmaceutically acceptable,” as used herein, meansthat the compositions or constituents thereof are suitable for use incontact with tissues or for use in patients in general without unduetoxicity, incompatibility, instability, allergic response, and the like.

The present active ingredients and formulations containing them inaccordance with the present disclosure can be injected into thesubmucosa of a polyp in amounts sufficient to treat the affected area.As used herein the word “treat,” “treating” or “treatment” refers tousing the active ingredients and/or compositions of the presentdisclosure prophylactically to prevent outbreaks of any undesirableconditions, or therapeutically to ameliorate an existing undesirablecondition. A number of different treatments are now possible, whichreduce and/or eliminate undesirable conditions.

As used herein “undesirable condition” refers to any detectable tissuemanifestations caused by a polyp or removal thereof. Such manifestationscan appear due to a number of factors such as, for example, traumaand/or other diseased or dysfunctional state. Non-limiting examples ofsuch manifestations include the development of bleeding, cancer,inflammation, flakiness and/or other forms of tissue abnormality, andcombinations thereof. It is understood, that the listed undesirableconditions are non-limiting and that only a portion of the conditionssuitable for treatment in accordance with the present disclosure arelisted herein.

Suitable polymers for use as the thermally responsive polymers inaccordance with the present disclosure include, but are not limited to,thermoreversible polymers, poloxamers, polyoxyalkylene block copolymers,alkyl cellulose, hydroxyalkyl cellulose, cellulosic ethers,poly(n-isopropylacrylamide), PEG triblock copolymers of L-lactide,glycolide, polyglycolides (PGA), copolymers of glycolides such asglycolide/lactide copolymers (PGA/PLLA) and/or glycolide/trimethylenecarbonate copolymers (PGA/TMC), D, L-lactide, L-polylactides (PLA),stereocopolymers of polylactides such as poly-L-lactide (PLLA),poly-DL-lactide copolymers and L-lactide/DL-lactide copolymers,ε-caprolactone, trimethylene carbonate (TMC), PEG-grafted chitosan,pectin-chitosan mixtures, methyl cellulose, gelatin, and combinationsthereof. Other suitable polymers include glycerin, dextrose, hyaluronicacid, hydroxypropyl cellulose, hydroxyethyl cellulose, hydroxyl propylmethyl cellulose (HPMC), combinations thereof, and the like.

The polymer may be dissolved in a solvent at a concentration of fromabout 10% to about 70% by weight of the solution, in embodiments fromabout 20% to about 60% by weight of the solution; thus the solvent maybe present in an amount from about 90% to about 30% by weight of thesolution, in embodiments from about 80% to about 40% by weight of thesolution. In embodiments, the polymer concentration may be such that thecomposition in accordance with the present disclosure is in a lowviscosity state at a pre-treatment temperature and a higher viscositystate at a treatment temperature that is higher than the pre-treatmenttemperature. The polymer concentration may also be such that thecomposition in accordance with the present disclosure is in a highlyviscous shear thinning state at a pre-treatment temperature and a higherviscosity state at a treatment temperature that is higher than thepre-treatment temperature.

As used herein, “pre-treatment temperature” refers to the temperature ofthe compositions in accordance with the present disclosure prior tobeing applied in the body of a patient, for example the submucosa of apolyp. The pre-treatment temperature may be room temperature, forexample from about 23° C. to about 25° C., or any temperature below thetreatment temperature. As used herein, “treatment temperature” refersgenerally to the temperature of the compositions in accordance with thepresent disclosure after being applied to the body, for example thesubmucosa of a polyp. The treatment temperature may be the normal bodytemperature for a human, for example about 37° C., or any temperaturefound within the body, including, for example, the temperature of apolyp to be treated. While the healthy human body can maintain a fairlyconsistent body temperature of about 37° C., the temperature may vary byabout ±2° C., with factors that may affect treatment temperatureincluding the age of the individual, the time of day, or the part of thebody in which the temperature is being measured at, and the like.

In embodiments, polyoxyalkylene polymers, including those commerciallyavailable under the tradename PLURONICS, may be utilized as thethermally responsive polymer. These polymers are commercially availablefrom BASF Corporation. Such polymers are closely related blockcopolymers classified as polyoxypropylene-polyoxyethylene condensatesthat terminate in primary hydroxyl groups, and may be formed by thecondensation of propylene oxide into a propylene glycol nucleus followedby the condensation of ethylene oxide onto both ends of thepolyoxypropylene base. The polyoxyethylene hydrophilic groups on theends of the base pre-polymer may be controlled in length so that theyaccount for from about 10% to about 80% by weight of the final polymer.The PLURONIC polymer series of products may be represented empiricallyby the formula: HO(C₂H₄O)_(a) (C₃H₆O)_(b) (C₂H₄O)_(c) H, where a and care statistically equal.

The thermally responsive polymer may include a mixture of otherpolyoxyalkylene polymers and/or various PLURONIC polymers. In someembodiments, a first block copolymer and a second block copolymer may beutilized. For example, a first block copolymer of ethylene oxide andpropylene oxide, such as PLURONIC F-127, may be mixed with a secondblock copolymer of ethylene oxide and propylene oxide, such as PLURONICF-68, in a solution. In some embodiments, the first block copolymer maybe present in amounts of from about 10% to about 50% by weight of thesolution. The first block copolymer such as PLURONIC-F-127 may have asolubility in water at about 4° C. of greater than about 10%. (Asconcentration increases, the gelation temperature decreases.) In otherembodiments, the first block copolymer may be present in amounts of fromabout 15% to about 30% by weight of the solution.

The second block copolymer, in embodiments F-68, may be present in anamount of from about 5% to about 50% by weight of the solution. Thesecond block copolymer, such as, for example, PLURONIC F-68, may have asolubility in water at about 4° C. of greater than about 10%. Inembodiments, the second block copolymer may be present in an amount offrom about 5% to about 25% by weight of the solution.

The first block copolymer, the second block copolymer, or both, may havea molecular weight of from about 7680 to about 14600. In embodiments,the first block copolymer may have a molecular weight of from about 7680to about 9510, while the second block copolymer may have a molecularweight of from about 9840 to about 14600.

In some embodiments, suitable compositions of the present disclosure mayinclude a solvent, from about 10% to about 50% by weight of a firstblock copolymer of ethylene oxide and propylene oxide, and from about 5%to about 50% by weight of a second block copolymer of ethylene oxide andpropylene oxide. In other embodiments, suitable compositions may includean aqueous solvent, and about 15% to about 50% by weight of a thermallyresponsive polymer admixture.

In embodiments, the first and second block copolymers may bethermoreversible. Suitable thermoreversible polymers may be added to thecompositions in accordance with the present disclosure in an amountsufficient to reversibly change the viscosity thereof in response tochanges in temperature. For example, a composition having a highviscosity at 37° C. may thin and have a low viscosity at 25° C., yetthicken again upon application of heat. Thus, such a composition may bea liquid at about 25° C. and a gel at a treatment temperature of about37° C.

In embodiments, thermoreversible polymers may be added to an aqueoussolution incorporating a stable combination or admixture of one or morethermoreversible polymers and/or thermally responsive polymers inamounts sufficient to effectively produce reversible gelation atpredetermined temperatures. As used herein, reversible gelation refersto the increase and/or decrease in the viscosity of a composition due toa variation in temperature, where the composition becomes a gel orgel-like at one temperature, and a liquid at another lower temperature.Non-limiting examples of suitable thermoreversible polymers for useherein include alkyl celluloses, hydroxyalkyl celluloses, cellulosicethers, PLURONIC® polymers and TETRONIC® polymers, and combinationsthereof. In embodiments, thermoreversible polymers may be added in anamount of from about 10% to about 50% by weight of the composition ofthe present disclosure.

In embodiments, compositions for use with a cannula in accordance withthe present disclosure may include hyaluronic acid and/or derivativesthereof, such as sodium hyaluronic acid. In other embodiments, thecompositions in accordance with the present disclosure may be devoid ofhyaluronic acid and/or derivatives thereof such as sodium hyaluronicacid, or hyaluronic acid or derivatives thereof combined with any otherchemical.

In embodiments, compositions in accordance with the present disclosuremay transition from a liquid state to a gel or gel-like state at atemperature of from about 5° C. to about 40° C., in embodiments at atemperature of from about 15° C. to about 37° C., and in otherembodiments at a temperature of from about 25° C. to about 35° C. Inembodiments, the transition temperature can be modified by includingpolymers such as PLURONIC F-68 in the composition.

Additionally, additives may be utilized to adjust the temperature atwhich the compositions of the present disclosure form a semi-solid,sometimes referred to herein as a gel. Any additive within the purviewof those skilled in the art may be utilized. The additives may behydrophilic or hydrophobic. In embodiments, suitable hydrophilicadditives include polyalkylene oxides such as polyethylene glycols (PEG)of varying molecular weights such as PEG 8000, PEG 10000 and the like,n-sodium octyl sulfate, n-sodium decyl sulfate, n-dodecyl sulfate,n-hexadecyl sulfate, n-octadecyl sulfate, combinations thereof, and thelike. Suitable other additives include, but are not limited to, saltssuch as NaCl, Na₂SO₄, CaCl₂, dyes such as methylene blue and isosulfanblue, antifoam agents, bioactive agents, combinations thereof, and thelike. For example, in some embodiments SURFYNOL® MD-20, a non-siliconesolvent-free liquid defoamer from Air Products and Chemicals, Inc.(Allentown, Pa.), may be added to adjust the gel temperature of acomposition of the present disclosure.

In yet other embodiments, surfactants may be added to compositions ofthe present disclosure to adjust the gel temperature. Suitablesurfactants are within the purview of those skilled in the art andinclude, for example, sorbitan esters, polyolefin based surfactants,ethoxylates, combinations thereof, and the like. In some embodiments,commercially available surfactants such as TRITON® 100 and TRITON® 114(nonionic surfactants from Sigma-Aldrich); TWEEN surfactants, SPANsurfactants, combinations thereof, and the like, may be utilized.Suitable TWEEN and SPAN surfactants include, but are not limited to,monolaureates (TWEEN 20, TWEEN 21, SPAN 20), monopalmitates (TWEEN 40,SPAN 40), monostearates (TWEEN 60, TWEEN 61, SPAN 60), tristearates(TWEEN 65, SPAN 65), monooleates (TWEEN 80, TWEEN 81, SPAN 80),trioleates (TWEEN 85, SPAN 85), combinations thereof, and the like.

Where utilized, the amount of such additives utilized to adjust the geltemperature of a composition of the present disclosure may vary fromabout 0.01% by weight to about 4% by weight of the composition, inembodiments from about 0.1% by weight to about 2.5% by weight of thecomposition, in embodiments from about 1% by weight to about 2.25% byweight of the composition, in other embodiments from about 1.5% byweight to about 2% by weight of the composition.

By adjusting the concentration of the copolymers and any additives,liquid to semi-solid transition temperatures between a pre-treatmenttemperature and a treatment temperature can be achieved. For example,the concentration of the thermally responsive polymers and the use ofadditives can be adjusted to provide compositions in accordance with thepresent disclosure that are a liquid at a pre-treatment temperature, anda gel at treatment temperature. In embodiments, the liquid-geltransition temperature may be from about 5° C. to about 65° C. In someembodiments, the constituents can be selected in predetermined amountsto produce high viscosity, shear thinning, gel compositions. Such highviscosity, shear thinning, compositions may be suitable for injection ina high viscosity state such as a gel. In embodiments, the compositionsin accordance with the present disclosure at 25° C. have a viscosity offrom about 50 centipoise to about 200,000 centipoise.

In shear thinning embodiments, compositions in accordance with thepresent disclosure transition from a semi solid and/or gel state to amore viscous semi-solid and/or gel state at a temperature from about 5°C. to about 50° C., in embodiments at a temperature from about 15° C. toabout 40° C., and in some embodiments at a temperature from about 30° C.to about 37° C. As compositions of the present disclosure may be used inthe human body, in embodiments it may be desirable for the compositionof the present disclosure to gel at a temperature close to human bodytemperature, which is about 37° C.

In other embodiments, a solvent utilized to form compositions for use inaccordance with the present disclosure may be water, saline, or anypharmaceutically acceptable solvent in amounts sufficient to solubilizethe ingredients of the composition. For example, a non-limiting exampleof a suitable solvent includes an aqueous solution such as saline,resuspension buffer such as a phosphate buffered saline, or a buffersuitable for injection into a patient. Non-limiting examples of solventsand/or buffers suitable for injection into a patient include apharmaceutically acceptable carrier such as a solution that does notcause allergic or other adverse reaction with the patient uponinjection. The solvent may be present in an amount of from about 30% toabout 90% by weight of the total composition. In embodiments, theconcentration of water in the composition can be from about 30% to about90% by weight of the composition, and/or from about 40% to about 80% byweight of the composition. The water used in forming the aqueoussolution may be purified, as by distillation, filtration, ion-exchange,and the like.

Other excipients can be added to the compositions of the presentdisclosure in amounts sufficient to promote the removal of one or morepolyps. For example, a dye may be added to the compositions to help thesurgeon see the polyp better during the removal process. Non-limitingexamples of suitable dyes include methylene blue, isosulfan blue, andcombinations thereof. Dyes may be added in an amount of about 0.1% toabout 2% by weight of the total composition.

Active ingredients can be added to the compositions of the presentdisclosure in amounts sufficient to benefit the patient and theprocedure for which the composition is provided, in embodiments apolypectomy procedure. While the amount of active agent used will dependon a number of factors including the specific active agent chosen andthe benefit to be achieved, generally, an amount of from about 0.01% toabout 10% by weight of the total composition may be suitable.Non-limiting examples of suitable active ingredients include enzymessuch as thrombin that converts fibrinogen to fibrin, vasoconstrictorssuch as epinephrine, norepinephrine, angiotensin, or vasopressin,chemotherapeutic agents such as fluorouracil (5-FU), antimicrobials,antibiotics, and combinations of these active agents.

In embodiments, compositions and product forms for use in accordancewith the present disclosure contain one or more active ingredients in aneffective amount to improve undesirable conditions. As used herein“effective amount” refers to an amount of a compound or compositionhaving active ingredients such as enzymes such as thrombin,vasoconstrictors such as epinephrine, norepinephrine, angiotensin, orvasopressin, chemotherapeutic agents such as fluorouracil (5-FU), andcombinations of these active agents in amounts sufficient to induce aparticular positive benefit to the polyp or tissue adjacent thereto. Thepositive benefit can be health-related. In embodiments, the positivebenefit may be achieved by contacting tissue with a coagulation proteinto promote clotting and closure of the excised tissue. In embodiments,the positive benefit may be achieved by contacting tissue with avasoconstrictor to reduce bleeding. In embodiments, the positive benefitis achieved by contacting tissue with a chemotherapeutic agent to killcancerous cells.

The pH of the compositions can be adjusted to from about 4 to about 8.Agents suitable for adjusting the pH of the compositions include, butare not limited to, buffering salts such as NaH₂PO₄, NaHPO₄, KH₂PO₄,K₂HPO₄, NaHCO₃, and Na₂CO₃, as well as mineral acids and bases such ashydrochloric acid and sodium hydroxide. The pH adjustment agents may bepresent in an amount of from about 0.01 to about 5% by weight of thetotal composition. In embodiments, the pH adjustment agent may bepresent in an amount of from about 0.1 to about 1% by weight of thetotal composition.

In embodiments, the cannulas of the present disclosure may be utilizedto introduce a composition for use in endoscopic polypectomy. Whereutilized in a polypectomy procedure, compositions may be applied to thesubmucosa of one or more polyps to improve presentation of the polyp andmake the polyp easier to capture with an endoscopic instrument such as asnare. For example, compositions having one or more thermoreversibleand/or thermally responsive polymers may be injected into the submucosaof a polyp to improve its presentation.

The use of a thermally responsive polymer in compositions of the presentdisclosure provides the ability to deliver or inject a liquid,gel-on-contact material to the submucosa of one or more polyps topromote removal thereof. As used herein, a gel refers to a semisolid orsemi-rigid system including a network of solid aggregates in whichliquid is held. By using a liquid delivery, it is possible to quicklyand efficiently treat a polyp with gelation upon delivery to the warmtissues. By introducing such materials by way of a multi-lumen cannulapossessing a coolant in one cannula, premature gelling of these polymersmay be avoided.

In embodiments, compositions in accordance with the present disclosuremay be shear thinning and show a decrease in viscosity with increasingrate of shear. Such shear thinning embodiments may be suitable forinjection into the submucosa of one or more polyps in a highly viscositystate such as a gel at pre-treatment temperatures. The application ofhighly viscous shear thinning compositions in accordance with thepresent disclosure provide the benefit of reducing and/or eliminatingtime needed for low viscosity compositions to become highly viscous uponwarming. In embodiments, highly viscous shear thinning compositions atthe pretreatment temperature may become even more viscous at thetreatment temperature. In embodiments, use of a shear thinningcomposition may reduce and/or eliminate a warming step needed to thickenthe compositions.

Polyps requiring removal may be pre-treated with one or morecompositions in accordance with the present disclosure which includesolvents and one or more polymers such as thermoreversible polymersand/or thermally responsive viscosity modifiers. These compositions maybe in a low viscosity state at a pre-treatment temperature and a higherviscosity or gel state at a treatment temperature that is higher thanthe pre-treatment temperature. In some embodiments additives may beincluded in the compositions of the present disclosure to further adjustthe temperature at which the composition forms a gel.

Preconditioning polyps by injecting the compositions in accordance withthe present disclosure into the submucosa of one or more polyps mayenhance the benefits of polypectomy, for example, by raising the polypswith a composition that gels or becomes more viscous when heated orapplied to a patient's warm body, and/or does not readily escape polypsafter initial incision thereof. Such preconditioning further improvesthe presentation of a polyp making it easier to grab and/or snare duringexcision.

In addition, treatment regimens in accordance with the presentdisclosure may improve a passage blocked by one or more polyps, and/orfacilitate the removal of tissue having a propensity to develop into acancerous lesion. Compositions in accordance with the presentdisclosure, at a pretreatment temperature and in a low viscosity stateprior to being injected, may be injected into the submucosa of one ormore polyps and allowed to warm to the treatment temperature such thatthe compositions increase in viscosity to a higher viscosity state suchas a gel. In embodiments, the viscosity of the compositions inaccordance with the present disclosure at the treatment temperature maybe higher then the viscosity of the compositions at the pre-treatmenttemperature. Treatment may then continue by removing the one or morepolyps while the more viscous compositions in accordance with thepresent disclosure remain substantially in the submucosa and to someextent in the polyp.

The various constituents of the compositions in accordance with thepresent disclosure may be combined with numerous ingredients to formproducts to be applied to the polyp, or other tissues of humans or othermammals.

It will be appreciated that various of the above-disclosed and otherfeatures and functions, or alternatives thereof, may be desirablycombined into many other different systems or applications. Also thatvarious presently unforeseen or unanticipated alternatives,modifications, variations or improvements therein may be subsequentlymade by those skilled in the art which are also intended to beencompassed by the following claims. Unless specifically recited in aclaim, steps or components of claims should not be implied or importedfrom the specification or any other claims as to any particular order,number, position, size, shape, angle, color, or material.

1-14. (canceled)
 15. A method of applying a composition comprising:obtaining a composition comprising a thermally responsive polymer,wherein the composition is in a low viscosity state at a pre-treatmenttemperature prior to being injected into a polyp and a higher viscositystate at a treatment temperature that is higher than the pre-treatmenttemperature; administering the composition to the polyp using amulti-lumen cannula comprising: a proximal end and a distal end; atleast one lumen configured to permit the passage of a coolant; and atleast a second lumen configured to permit the passage of the compositioncomprising the thermally responsive polymer; warming the compositionthereby increasing the composition's viscosity to the higher viscositystate, and removing the polyp while the composition comprising thethermally responsive polymer remains substantially inside the polyp. 16.The method of claim 15, wherein the cannula comprises a coaxial doublelumen cannula comprising an inner lumen possessing the compositioncomprising the thermally responsive polymer and an outer lumenpossessing the coolant.
 17. The method of claim 16, wherein the distalend of the outer lumen of the cannula possesses a device selected fromthe group consisting of valves, stoppers and seals, to prevent thecoolant from exiting the distal end of the cannula.
 18. The method ofclaim 16, wherein the distal end of the inner lumen of the cannulapossesses a dispensing needle.
 19. The method of claim 15, wherein thecoolant is selected from the group consisting of water, saline, air,nitrogen, argon, helium, carbon dioxide, ethanol, and combinationsthereof.
 20. The method of claim 15, wherein the coolant comprises asolution selected from the group consisting of ammonium nitrate crystalsin water, potassium iodide in water, ammonium chloride in water,ammonium acetate in water, potassium thiocyanate in water, ammoniumthiocyanate in water, sodium thiosulfate in water, ammonium bromide inwater, urea based solutions, and combinations thereof.
 21. The method ofclaim 15, wherein the composition comprising the thermally responsivepolymer is selected from the group consisting of alkyl cellulose,hydroxyalkyl cellulose, cellulosic ethers, poloxamers, polyoxyalkyleneblock copolymers, poly(n-isopropylacrylamide), PEG triblock copolymersof L-lactide, glycolide, polyglycolide, copolymers of glycolide,glycolide/lactide copolymers, glycolide/trimethylene carbonatecopolymers, D, L-lactide, L-polylactides, poly-L-lactide,poly-DL-lactide copolymers, L-lactide/DL-lactide copolymers,.epsilon.-caprolactone, trimethylene carbonate, PEG-grafted chitosan,pectin-chitosan mixtures, methyl cellulose, gelatin, thermoreversiblepolymers, and combinations thereof.
 22. The method of claim 15, whereinthe composition comprising the thermally responsive polymer comprises asolvent and from about 10% to about 50% by weight of one or morethermally responsive viscosity modifiers comprising a mixture of a firstblock copolymer of ethylene oxide and propylene oxide and a second blockcopolymer of ethylene oxide and propylene oxide.
 23. The method of claim22, wherein the composition comprising the thermally responsive polymercomprises a first block copolymer having an average molecular weight offrom about 7680 to about 14600 present in an amount of about 10% toabout 50% by weight of the total composition, in combination with asecond block copolymer having an average molecular weight of from about7680 to about 14600 present in an amount of from about 5% to about 50%by weight of the total composition.
 24. The method of claim 15, whereinthe composition comprising the thermally responsive polymer furthercomprises one or more active ingredients selected from the groupconsisting of enzymes, vasoconstrictors, chemotherapeutic agents,antimicrobials, antibiotics, and combinations thereof.
 25. The method ofclaim 15, wherein the composition comprising the thermally responsivepolymer has a viscosity of from about 50 centipoise to about 200,000centipoise at about 25° C.
 26. The method of claim 15, wherein thecomposition comprising the thermally responsive polymer is a liquid at apre-treatment temperature of about 25° C. and a gel at a treatmenttemperature of about 37° C.